Method for Treating Glioma with Ohsv2

The present disclosure relates to the technical field of biological medicine, specifically to a recombinant oncolytic herpes simplex virus type II (oHSV2) and a method for treatment of central nervous system tumors, specifically for treatment of glioma, and more specifically, for treatment of a recurrent glioma, with the oHSV2.

Glioma, accounting for approximately 46% of intracranial tumor cases, is one of the most common primary malignant tumors occurring at the central nervous system. With the highest morbidity among brain tumors, glioma presents a peak of onset age between 30 to 40, or 10 to 20 years old overall. Glioma is of strong aggressiveness, frequent recurrence, and high mortality. At present, the clinical treatment of glioma is mostly based on post-surgical radiotherapy and chemotherapy. However, glioma is resistant to many chemotherapeutic drugs due to different sensitivities against anti-tumor drugs between different individuals, thus resulting in unsatisfactory clinical efficacies.

Glioblastoma multiforme (GBM) is one of the most common malignant primary tumors in brain, the initial standard treatments for which are surgical resection and post-surgical radiotherapy. However, for most patients GBM will recur regardless of which treatment initially adopt, and there are no standard chemotherapy regimens for recurrent glioma after the initial standard treatments. It is still palliative for salvage chemotherapy regimens with single-agent or drug combinations for the recurrent high-grade gliomas of patients, whose median survival is from 6 to 8 months, and very few of them survive more than 2 years. The guidelines on the diagnosis and treatment of gliomas (2022 edition) recommends that for the high-grade recurrent gliomas, clinical trials are strongly advised as a matter of priority, and in the absence of an appropriate clinical trial, the following regimens may be used: a. bevacizumab; b. temozolomide; c. lomustine or carmustine; d. PCV regimen; e. regorafenib; f. bevacizumab plus chemotherapy with carmustine/lomustine or temozolomide; g. etoposide; h. carboplatin or cisplatin-based chemotherapy regimen; i. corresponding target-specific drugs recommendable for patients with BRAF V600E activating mutation or NTRK fusion.

Oncolytic viruses are a class of natural or gene-edited viruses that can specifically replicate in tumor cells and exert anti-tumor effects, and one of them, recombinant oncolytic herpes simplex virus, is an oncolytic virus with development potential for use in cancer immunotherapy. Currently, four oncolytic viral therapies are available around the world, in which adenoviruses, herpesviruses, reoviruses and cowpox viruses are most commonly used, accounting for 31%, 24%, 20% and 12.5% respectively. In June, 2021, oncolytic herpes simplex virus type I, Delytact (G47Δ), provided by Daiichi Sankyo in Japan, was approved for the treatment of malignant glioblastoma. Clinical data showed that the survival rates of malignant glioma patients treated by G47Δ had significantly improved compared with that treated by conventional therapies. However, G47Δ still has the disadvantages of high administration dosage, complex administration means and the need for synchronous administration of other drugs for the treatment.

Therefore, there is an urgent need for providing a new drug and a method for the treatment of patients with brain glioma, by the new drug.

Regarding the deficiencies of the related art, in view of the limited therapeutic effects of currently approved drugs for the treatment of glioma, especially malignant glioma, an object of the present disclosure is to provide an antitumor drug with improved treatment efficacy, which is assessed by indicators such as “Objective Response Rate (ORR)”, “Disease Control Rate (DCR)”, “Median Overall Survival (mOS)” and the like, and with fewer side effects for patients suffering from glioma.

Surprisingly, the inventors found that the recombinant oncolytic herpes simplex virus type II (oHSV2) shows an excellent therapeutic effect on glioma in clinical trials, in the form of an injection, indicating that the oHSV2 can effectively treat glioma, especially malignant glioma. More specifically, the oHSV2 also function effectively in subjects intolerant to one or both of chemotherapy and radiotherapy and/or resistant to treatment at least two lines of previous therapy. For the purpose of the present disclosure, the oHSV2, including a stable genomic sequence of a recombinant oncolytic herpes simplex virus type II as described in patent No. CN102146418B, refers to the modified herpes simplex type II virus obtained according to the method therein. As used herein, the term “oHSV2” refers to a recombinant oncolytic herpes simplex virus type II as disclosed in patent No. CN102146418B and Zhao Q, Zhang W, Ning Z, Zhuang X, Lu H, Liang J, Li J, Zhang Y, Dong Y, Zhang Y, Zhang S, Liu S, Liu B. A novel oncolytic herpes simplex virus type 2 has potent anti-tumor activity. PLoS One. 2014 Mar. 26; 9 (3): e93103. doi: 10.1371/journal.pone.0093103. PMID: 24671154; PMCID: PMC3966855. Meanwhile, the oHSV2, as an oncolytic virus capable of killing tumor cells, should be interpreted as an antitumor drug in the particular context of the present disclosure. The entire disclosure of patent No. CN102146418B is incorporated herein by reference.

To realize the above object, the present disclosure provides the following technical solutions.

In a first aspect, the present disclosure, in embodiments, provides an antitumor drug for a central nervous system tumor, such as glioma including brain glioma and the like. The antitumor drug includes recombinant oncolytic herpes simplex virus type II (oHSV2) as active ingredient, which is named as H2d3d4-hGF, with a proposed taxonomic designation of Herpes Simplex Virus Type 2, and is deposited in depository authority of China General Microbiological Culture Collection Center located in Institute of Microbiology, Chinese Academy of Sciences, Building No. 3, Yard No. 1, West Beichen Road, Chaoyang District, Beijing, China, on Feb. 3, 2010, with an accession number of CGMCC No. 3600. Specifically, the oHSV2 is obtained by knocking out genes ICP34.5 and ICP47 of a wild herpes simplex virus type II strain HG52, and inserting a human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cassette at the position of the knocked out gene ICP34.5.

In some embodiments, the antitumor drug is an oHSV2 injection.

In a second aspect, the present disclosure provides a method for treating a subject with a central nervous system tumor, including: administering the subject a therapeutically effective amount of an antitumor drug, where the antitumor drug contains recombinant oncolytic herpes simplex virus type II (oHSV2), which is named as H2d3d4-hGF, with a proposed taxonomic designation of Herpes Simplex Virus Type 2, and is deposited in depository authority of China General Microbiological Culture Collection Center located in Institute of Microbiology, Chinese Academy of Sciences, Building No. 3, Yard No. 1, West Beichen Road, Chaoyang District, Beijing, China, on Feb. 3, 2010, with an accession number of CGMCC No. 3600.

In some embodiments, the central nervous system tumor is a recurrent central nervous system tumor.

In some embodiments, the central nervous system tumor is glioma.

In some embodiments, the glioma is glioblastoma.

In some embodiments, the central nervous system tumor is brain glioma.

In some embodiments, the subject is intolerant to one or both of chemotherapy and radiotherapy.

In some embodiments, the subject is resistant to treatment at least two lines of previous therapy, wherein the at least two lines of previous therapy are selected from first-line, second-line, third-line therapies and immunotherapy beyond line.

In some embodiments, the subject is over 18 years of age.

In some embodiments, for each treatment cycle, the antitumor drug is administered once every 3 weeks, with administration times of ≥3.

In some embodiments, the oHSV2 in the antitumor drug is administered with a single dose from 10CCID/ml to 10CCID/ml.

In some embodiments, the antitumor drug is administered a single dose or multiple doses.

In some embodiments, the oHSV2 in the antitumor drug is administered with a single dose from 10CCID/ml to 10CCID/ml with a single administration volume of ≤2 ml.

In some embodiments, the oHSV2 in the antitumor drug is administered with a single dose of 10CCID/ml or 10CCID/ml with a single administration volume of ≤2 ml.

In some embodiments, the oHSV2 in the antitumor drug is administered with a single dose lower than 2*10CCID.

In some embodiments, the antitumor drug is in form of an injection, the method specifically includes: administering the antitumor drug by intratumor injection.

In some embodiments, the oHSV2 in the antitumor drug is formulated in a pharmaceutically acceptable solution.

In some embodiments, the antitumor drug is administered by a direct subcutaneous injection or an ultrasound-guided intratumor injection.

In some embodiments, Ommaya reservoir is used as a device for administering the antitumor drug into the subject.

In some embodiments, the antitumor drug is used in a combination with other antitumor drugs, supportive antitumor drugs and/or drug excipients.

In some embodiments, the oHSV2 is obtained by knocking out genes ICP34.5 and ICP47 in a wild herpes simplex virus type II strain HG52 and inserting a human granulocyte-macrophage colony-stimulating factor (hGM-CSF) cassette at the position of the knocked out gene ICP34.5.

The present disclosure provides an antitumor drug for a central nervous system tumor, such as a brain glioma, and the drug may be an injection containing the oHSV2.

Compared to the related art, the antitumor drug provided by the present disclosure has at least the following beneficial effects.

In order to make the object, technical solution and advantages of the present disclosure more clearly understood, the present disclosure is further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only intended to explain the present disclosure but not to limit the present disclosure.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

Unless defined otherwise, all scientific and technical terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The term “oHSV2 injection” refers to oHSV2 in the form of injection. The term “injection” refers to a sterile solution containing drug and for injecting administration into the body, which includes an emulsion and suspension, as well as sterile powders or a concentrated solution containing drug and for preparation into a solution or suspension before use. The injection works rapidly and reliably and is free from influences of pH, enzymes, food, etc. as well as the first-pass effect, enabling systemic or local effects, and is therefore suitable for patients who are unfit for or cannot perform oral administration of drugs. In the present disclosure, the terms “injection” and “injection preparation” are equivalent in definition.

The terms “Complete Response (CR)”, “Partial Response (PR)”, “Stable Disease (SD)”, “Progressive Disease (PD)” refers to four assessment levels in terms of therapeutic efficacy on tumors (solid tumors only). Specifically, the term “CR” refers to all target lesions have disappeared, no new lesion appears, and a tumor markers are normal, with all of these maintaining for at least 4 weeks; “PR” refers to the sum of the largest diameters of target lesions has been reduced by ≥30%, and maintained for at least 4 weeks; “SD” refers to the sum of the largest diameters of target lesions is reduced but not reaching the criteria of PR, or increased but not reaching the criteria of PD; and “PD” refers to the sum of the largest diameters of target lesions has been increased by at least ≥20%, or new lesions appear.

The terms “Objective Response Rate (ORR)” and “Disease Control Rate (DCR)” refer to associated indicators for assessing the therapeutic efficacy on tumors (solid tumors only). Generally, “ORR” refers to the proportion of subjects whose tumor volumes have reduced by at least 30% and maintained for 4 weeks, that is to say, the sum of the proportions of subjects in CR and PR. The higher the ORR, the more subjects under the treatment having tumor reduced. “DCR” refers to the proportion of subjects that achieve CR+PR and SD under the treatment, i.e., the proportion of subjects who do not experience PD.

The term “Median Overall Survival (mOS)”, also known as half-survival in medicine, refers to the survival time corresponding to a cumulative survival rate of 50%, representing only 50% of the individuals being survival at this point. The mOS is an indicator for assessing the therapeutic efficacy of cancer subject in terms of survival, and is generally used to determine the prognosis of subjects with malignant tumors, where the longer the mOS, the longer overall survival time of subjects with malignant tumors. The mOS may also be used to determine the therapeutic efficacy of a new program. If subjects undergoing a certain treatment program is found to have a prolonged mOS or a significantly improved mOS than that of current standard treatment programs, generally such a new treatment program would be recommended or applied to clinical treatment, so as to bring certain benefits to the subjects such as increasing the survival rate of the subjects and improving the life quality of the subjects.

In embodiments of the present disclosure, the term “preferred” is only used for describing a more effective embodiment or example, and should not constitute a limitation on the protection scope of the present disclosure.

In embodiments of the present disclosure, the technical features described with an open manner both include a technical solution consisting of the enumerated features, and a technical solution including the enumerated features.

In embodiments of the present disclosure, when numerical intervals are involved, unless otherwise specified, endpoints of the numerical interval are included.

In embodiments of the present disclosure, an antitumor drug comprising oHSV2 may in addition comprise at least one pharmaceutically acceptable excipient/solution, e.g. carrier or diluent, e.g. including fillers, binders, disintegrators, flow conditioners, lubricants, sugars and sweeteners, fragrances, preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizers, salts for regulating osmotic pressure and/or buffers.

In embodiments of the present disclosure, first-line, second-line, third-line therapies and immunotherapy beyond line (also named as immunotherapy beyond progression, IBD) may refer to antineoplastic protocols for respective cancers recommended in the related art.

Recombinant oncolytic herpes simplex virus type II (referred to as oHSV2 later) can selectively infect and replicate itself in the tumor cells, ultimately lysing and killing the tumor cells, as well as releasing progeny viral particles to infect the surrounding tumor cells further. This process also contributes to the release of tumor-associated antigens (TAAs).

The anti-tumor effect of the oHSV2 not only lies in directly killing the tumor cells by viral replication or the direct toxicity of viral proteins, but also in the regulation to the immunosuppressive tumor microenvironment, which is conducive to breaking the immune tolerance thereby triggering anti-tumor immune responses, where lysis of the tumor cells results in releases of TAAs, thereby inducing systemic anti-tumor immune responses in the body, according to recent studies.

After extensive and in-depth research, the inventors have applied the oHSV2 and its injection into the treatment of glioma for the first time. Results of the clinical trials proved the effectiveness of the oHSV2 and its injection in the treatment of glioma. On the basis of such research and clinical trials, the present disclosure is provided.

Research on oHSV2 Injection and Anti-Tumor Mechanism Thereof

The recombinant oncolytic herpes simplex virus type II (oHSV2) injection provided in the present disclosure is obtained by subjecting a wild herpes simplex virus type II to modifications of knocking out neurotoxin and immunosuppressive genes and inserting immune-enhancing factor genes into the viral genome, with molecular cloning, DNA homologous recombination, and other techniques. The knock-out of neurotoxin genes enables the oHSV2 to selectively replicate in tumor cells with impaired PKR signaling pathway and expand to infect the surrounding tumor cells, rather than replicate in normal cells, which results in significantly decreased virulence and reduced drug side effects. The knock-out of the immunosuppressive genes facilitates the activation of anti-tumor immune responses. These two modifications enhance the oncolytic activity of the virus. In addition, insertion of hGM-CSF cassette induces differentiation, proliferation and maturation of tumors and their surrounding dendritic cell (DC) precursors, as well as enhances antigen presenting of DC to activate immune killer cells in vivo, which contributes to inducing local and systemic anti-tumor immune responses. It also ensures the oncolytic activity of the oHSV2 and increases its druggability along with immune activation.

The oHSV2 and injection thereof provided in an embodiment of the present disclosure contain a recombinant oncolytic herpes simplex virus type II, which is named as H2d3d4-hGF, with a proposed taxonomic designation of Herpes Simplex Virus Type 2, and is deposited in depository authority of China General Microbiological Culture Collection Center located in Institute of Microbiology, Chinese Academy of Sciences, Building No. 3, Yard No. 1, West Beichen Road, Chaoyang District, Beijing, China, on Feb. 3, 2010, with an accession number of CGMCC No. 3600.